JPH02503672A - Fatty acids and their short chain esters as penetration enhancers in aqueous systems - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] As a penetration enhancer in aqueous systems fatty acids and their short chain esters [Background of the invention] The present invention provides therapeutically suitable dosages of components having therapeutic activity in the systemic circulatory system of mammals. For transdermal delivery of Concerning suitable pharmaceutical compositions.

In certain and preferred applications, therapeutically active ingredients or opioids may be added. Drugs such as odoids are preferred active ingredients in the transdermal delivery systems described above. You may choose.

Because many drugs are initially metabolized by the liver and intestines, mammalian systemic circulation Many opioids are known to have poor bioavailability in the system. Furthermore, opio When administered orally, hydration may occur due to various factors such as changes in acidity and food contents. Because the amount of drug absorbed in the gastrointestinal tract varies, its bioavailability is unpredictable. stomach. Furthermore, if the drug is administered orally, patients do not always comply with the instructions.

Opioids have better bioavailability when administered parenterally than when administered orally. Ru. However, various parenteral treatments such as intravenous, intramuscular, and subcutaneous delivery The intestinal route of administration is not convenient for long-term therapy. This is especially true when biological activity is halved. This applies well to short-lived opioids.

Topical opioid prescriptions do not necessarily deliver therapeutically effective amounts of drug to the systemic circulation. bioavailability may be poor or unpredictable.

In the literature regarding the topical formulation of drugs used for the purpose of local anesthesia, saturation or Natural oils containing unsaturated fatty acids have been described.

Transdermal delivery of opioid drugs to the mammalian systemic circulatory system has the following advantages: It is described as an example of a method of administration.

1. With transdermal delivery, there is no initial metabolism of the drug by the liver or intestines, and the gastrointestinal tract It also avoids unmeasurable absorption, making it easier to administer opioids compared to oral administration. Bioavailability is higher and predictable.

2. The drug concentration in the serum is stable, so it is a long-lasting drug that is equivalent to intravenous infusion. Physical effects can be obtained.

3. The administration rate can be easily adjusted, maximizing drug efficacy and minimizing side effects. You can

4. Drug source can be easily removed, allowing for discontinuation of administration and elimination of drug in body fluids. Elimination can be done quickly.

5. Because administration is simple, patients can use it more comfortably compared to parenteral administration, and oral administration is more convenient. Comparatively, patients' compliance with usage instructions is improved.

Transdermal drug delivery differs from topical drug delivery in that transdermal prescriptions Specifically designed for delivery to the systemic circulatory system at a rate that is understandable and primordially meaningful. In contrast, topical prescriptions have a therapeutic effect only in the local area where the drug is applied. The point is that it is specially designed to do so. In addition, topical formulations may cause side effects. In order to minimize stomach. However, even when local delivery of drugs results in systemic absorption, the circulatory system The amount of drug supplied to the patient varies widely and cannot be controlled.

European Patent Publication No. 0171742 describes the use of saturated or unsaturated aliphatic alcohols in Used in acid or ester form with a carrier such as propylene glycol. transdermal delivery of opioids in organic systems, i.e. suspensions or gels. The first system is described. The drawback to this system is that propylene glycol or other The use of organic solvents is known to cause skin irritation.

This time saturated or unsaturated fatty acids or their esters, such as linoleic acid, were It is effective as a skin absorption enhancer in aqueous systems and is therefore non-irritating to the skin. It has been found that a new and effective transdermal composition can be obtained.

[Summary of the invention]

Therefore, the present invention includes the following components: A therapeutically effective amount of the drug or a pharmaceutically acceptable salt thereof; saturated with 8 to 18 carbon atoms. or unsaturated fatty acids or their 01-C4 alkyl esters, and pharmaceutically acceptable excipients, administration of a therapeutically effective amount of the drug to the systemic circulatory system of a mammal, consisting of an aqueous suspension containing PHARMACEUTICAL COMPOSITIONS Suitable for Dermal Delivery.

Another embodiment of the invention comprises, in an aqueous suspension, the following ingredients: A therapeutically effective amount of the drug or a pharmaceutically acceptable salt thereof; saturation of C6-C11 carbon atoms; an effective amount of a saturated or unsaturated fatty acid or its C,-C,alkyl ester; and pharmaceutically acceptable excipients; administration of a therapeutically effective amount of a drug to the mammal's systemic circulatory system. The present invention relates to a method for transdermal delivery.

[Description of preferred embodiments]

The aqueous transdermal compositions of the present invention include any drug combination, including The composition is preferably utilized especially when using an opioid as the drug.

The term "opioid" includes morphine, oxymorphone, fuentanil, natural or synthetic such as meperidine, propoxyphene, or oxycodone Opioid pain relievers; such as nalmefene, naloxone or naltrexone natural or synthetic narco-tic antagonist ; such as nalmefene, butorphanol, propnorphine or bentazocine. natural or synthetic mixed opioid agonists/antagonists; or This refers to any of these salts that are acceptable.

The term "pharmaceutically acceptable salts" refers to salts that have therapeutic efficacy in mammals. Any non-toxic pharmaceutically acceptable salt of an opioid is meant. this Methods for preparing such salts are well known to those skilled in the pharmaceutical field. pharmaceutically Acceptable salts of opioids are acetate, naphthylate, tosylate, succinate. , hydrochloride, valmitate, stearate, oleate, bamoate, lau Phosphoric acid, valeric acid, hydrobromide, sulfate, methanesulfonate, tartrate, quench Includes phosphate and maleate salts.

The term "saturated or unsaturated fatty acids of 8 to 18 carbon atoms" means of such acids or their esters effective in facilitating their passage through the skin. It also means deviation. Preferred examples are linoleic acid and oleic acid and It is a Cl-04 alkyl ester.

Linoleic acid is most preferred.

Pharmaceutically acceptable excipients can be applied to the skin itself or as a band-aid, tape, Creams or lotions suitable for administration via known materials such as batches etc. Other materials used in the composition to bind the loading component to the composition. Ru. These excipients include, for example, Carpopol 934, Carpopol 940, Carpopol Popol 941 (B, F, Goodrich and Co, acrylic acid, water soluble The molecular weight is 3,000,000.4,000,00 respectively. 0 and 1.250,000): Tween 20 (US 1cI), Polyso rubate 20, polyoxyethylene 20 sorbitan monorathalate, or other tweens such as tween 40, tween 60 and tween 80, and and other pharmaceutically acceptable emulsifiers such as polyethylene glycol esters. eg polyethylene glycol monolaurate can also be used.

The effectiveness of the present invention is that linoleic acid can be absorbed from organic and aqueous absorption promoting systems containing The following examples compare the penetration of oxomorphone through the skin of hairless mice; This will be explained using the results presented in table format.

aqueous system LA 30% (0.3% Capo Ball + 2.5% Tween 20) 70% 667.45 6.8 LA 20% (0.3% Capopole + 2.5% Tween 20) 80% 636.11 9.3 LA 10% (0.3% Capopole + 2.5% Tween 20) 90% 672.76 4.3 LA 5% (0.3% Capopole + 2.5% Tween 20) 95% 543.82 9.5 LA 20% (2.5% Tween 20) 80% 884.46 4.40.3% capo ball 38. 31 170.3% Capopole + 2.5% Nyen 20 19.73 15.61PG-Propylene Glycol TA-) Liacetin Note: Because aqueous systems are suspensions, they routinely contain a maximum availability or permeability (i.e. maximum flux); therefore, organic systems and It was necessary to calculate the maximum flux values for comparison with the degree data. Li Nolic acid: Propylene glycol: 0.5% ximole in triacetin mixture The saturation solubility of oxymorphone in each system is determined using the permeability coefficient of the phon solution. The maximum flux was calculated by multiplying by the corresponding permeability coefficient. However, water For a chemical suspension (5% W/W drug), the graph of cumulative average concentration of drug vs. time shows steady state. was not observed, so the flux values for aqueous systems are expected to be higher. .

As shown in the table, the aqueous system containing the model fatty acid, namely linoleic acid, It effectively promoted the skin permeation of drugs. The usual dosage of oxymorphone is 6-1 0+119/day, and this amount is equivalent to linoleic acid-containing water from 1OcI112 patch. It can be said that sufficient supply can be achieved using either system.

Corrected sound translation submission form (Article 184-8 of the Patent Act) November 30, 1989

Claims (1)

[Claims] 1) The following ingredients: a therapeutically effective amount of the drug or a pharmaceutically acceptable salt thereof; Saturated or unsaturated fatty acids having 8 to 18 carbon atoms or C1 to C4 alkyl thereof an ester, and a pharmaceutically acceptable excipient; administration of a therapeutically effective amount of the drug to the systemic circulatory system of a mammal, consisting of an aqueous suspension containing Pharmaceutical compositions suitable for dermal delivery. 2) The composition according to claim 1, wherein the drug is an opioid. 3) If the opioid is morphine, oxymorphone, fendanyl, meperidine, or Natural or synthetic opioid pain relief, such as lopoxifen, or oxycodone Agents: natural or synthetic such as nalmefene, naloxone or naltrexone Narcotic antagonists; nalbufin, butorphanol, buprenorphin or penta a natural or synthetic mixed opioid agonist/antagonist such as Zosyn; or The composition according to claim 2, which is a pharmaceutically acceptable salt thereof. 4) The composition according to claim 3, wherein the opioid is oxymorphone. 5) The composition according to claim 1, wherein the fatty acid is oleic acid or oleic acid. 6) A composition according to claim 1, wherein the aqueous suspension contains from 0.1 to 10% by weight of drug. . 7) The aqueous suspension contains a saturated or unsaturated fatty acid having 8 to 18 carbon atoms or its C The composition of claim 1 containing from about 1 to about 30% by weight of 1-C4 alkyl ester. . 8) The aqueous suspension contains linoleic acid or oleic acid or a C1-C4 alkyl thereof. 8. The composition of claim 7, containing from about 1 to about 20% by weight of the ester. 9) The composition of claim 7, wherein the aqueous thread contains from about 1 to about 30% by weight linoleic acid. . 10) The composition of claim 7, wherein the aqueous system contains about 10-20% by weight of linoleic acid. thing. 11) In the aqueous suspension, the following ingredients: a therapeutically effective amount of the drug or a pharmaceutically acceptable salt thereof; Saturated or unsaturated fatty acids of C8 to C18 carbon atoms or C1 to C4 alkyl thereof an effective amount of the ester, and a mulberry-acceptable excipient; administration of a therapeutically effective amount of a drug to the mammal's systemic circulatory system. Methods for transdermal delivery.